Elevation of glomerular capillary pressure is a major risk factor for hypertensive renal injury. Ang II hypertension impairs autoregulation and eliminates P2X1 receptor- mediated vasoconstriction, which is critically important for mediating afferent arteriolar autoregulatory behavior. Impaired autoregulation in hypertension coincides with increased renal cytokine production, such as TGF-2 and MCP-1, which may be involved in hypertension-induced renal microvascular dysfunction. Project 2 will determine the role of these cytokines on afferent arteriolar dysfunction in Ang II infused hypertension. Preliminary data indicate that anti-inflammatory treatment prevents afferent arteriolar dysfunction in hypertension. TGF- 2 inhibits autoregulatory responses. Furthermore, MCP-1 inhibition with CCR2 receptor blockade improves autoregulatory efficiency in hypertensive kidneys. These data support the central hypothesis of Project 2 that hypertension initiates intrarenal inflammatory events that result in afferent arteriolar dysfunction and renal injury by impairing P2X1 receptor signaling. Ang II-infused hypertensive rats will be treated with the anti-inflammatory agents, pentosan polysulfate or mycophenolate mofetil, to inhibit inflammatory processes. Experiments will establish the impact of anti-inflammatory treatment on impaired arteriolar autoregulatory behavior, reduced afferent arteriolar reactivity to P2 receptor stimulation, preglomerular vascular smooth muscle Ca2+ signaling mechanisms and expression and function of ROS and intrarenal inflammatory mediators in hypertensive and normotensive rats. These objectives will be addressed in the following specific aims. Specific aim 1 will test the hypothesis that hypertension-induced inflammatory processes impair afferent arteriolar autoregulatory behavior in Ang II-infused hypertensive rats. Specific aim 2 will test the hypothesis that hypertension-induced inflammatory processes impair afferent arteriolar P2X1 receptor reactivity in Ang II-infused hypertensive rats. Specific aim 3 will test the hypothesis that MCP-1 contributes significantly to the hypertension induced afferent arteriolar dysfunction and impaired Ca2+ signaling mechanisms that occur in Ang II- infused hypertension. Specific aim 4 will test the hypothesis that hypertension-induced increases in TGF-2 and ROS contribute significantly to the decline in afferent arteriolar function. These studies will provide new mechanistic information linking chronic inflammatory events with suppression of autoregulatory function, impairment of Ca2+ signaling and renal microvascular reactivity to P2X receptor stimulation and they will demonstrate that suppression of inflammatory events leads to improved renal microvascular function and renal protection in hypertension.